Variant Reclassification Analysis

Investigation of Pathogenic to Benign Reclassifications

Generated: 2025-10-19 23:26:40

Table of Contents

Summary Statistics

Total Variants
35
P→B Variants
21
Genes with P→B
10
Median Time to Benigning
71.1 mo
Inter-lab Flips
100.0%
Top Reason
Other/Unknown

Gene & Variant Landscape

Distribution of P→B reclassifications across genes and their characteristics.

Top Genes by P→B Variant Count
Genes with the highest number of variants reclassified from pathogenic to benign.
Gene Landscape: Count vs Time to Benigning
Bubble size represents median time to reclassification. Minimum size applied for visibility.

Classification Flow & Timing

Temporal patterns in variant reclassifications.

Classification Flow Diagram
Movement from pathogenic to benign classifications, split by inter-lab vs intra-lab changes.
Reclassification Timeline
Temporal distribution of initial P/LP and subsequent B/LB classifications.

Reasons for Reclassification

Inferred reasons driving P→B reclassifications based on ACMG evidence codes.

Primary Reasons for Reclassification
Distribution of reason categories across P→B variants.
Reason Distribution by Submitter
Heatmap showing which submitters contribute to each reclassification reason.

Submitter Dynamics

Analysis of submitter patterns in reclassifications.

Top Submitters on Benign Side
Laboratories most frequently submitting benign classifications for P→B variants.
Inter-lab vs Intra-lab Reclassifications
Proportion of reclassifications within same vs different laboratories (excludes cases with missing submitter data).

Detailed Variant Table

Complete list of all P→B variants with classification details and inferred reclassification reasons.

Showing all 21 P→B variants sorted by gene and time to benigning. Table is scrollable. The 'inferred_reasons' column shows the likely drivers of reclassification based on ACMG evidence changes.

gene variant type first_plp_date first_blb_date first_plp_submitter first_blb_submitter time_to_benign_months interlab plp_codes blb_codes inferred_reasons
BRCA2 NM_000059.4(BRCA2):c.8187G>T (p.Lys2729Asn) missense 2002-07-26 2011-03-14 OMIM Sharing Clinical Reports Project (SCRP) 103.6 True Other/Unknown
BRCA2 NM_000059.4(BRCA2):c.7879A>T (p.Ile2627Phe) missense 2012-03-11 2019-09-01 Sharing Clinical Reports Project (SCRP) King Laboratory, University of Washington 89.7 True Other/Unknown
BRCA2 NM_000059.4(BRCA2):c.891_899delinsGATACTTAG (p.Thr298_Val300delinsIleLeuArg) missense 2017-04-20 2023-03-23 Department of Pathology and Molecular Medicine, Queen's University University of Washington Department of Laboratory Medicine, University of Washington 71.1 True PM1,PM2,PP4 BP1 Guideline/model change
BRCA2 NM_000059.4(BRCA2):c.8851G>T (p.Ala2951Ser) missense 2020-04-08 2025-05-16 Center of Medical Genetics and Primary Health Care Ambry Genetics 61.2 True PM1,PM2,PP3,PP4 BP2,BP4,BP5,BP7,BS1,BS2,BS3,BS4 Population frequency, New benign functional evidence, Computational shift
BRCA2 NM_000059.4(BRCA2):c.2623G>C (p.Val875Leu) missense 2020-04-08 2023-03-23 Center of Medical Genetics and Primary Health Care University of Washington Department of Laboratory Medicine, University of Washington 35.4 True BP4,PM1,PM2,PP1,PS1 BP4,BS1 Population frequency, Guideline/model change
COL4A5 NM_033380.3(COL4A5):c.2692A>G (p.Met898Val) missense 2019-02-14 2019-06-15 Yale Center for Mendelian Genomics, Yale University PreventionGenetics, part of Exact Sciences 4.0 True Other/Unknown
HNF1A NM_000545.8(HNF1A):c.1748G>A (p.Arg583Gln) missense 2002-10-01 2016-10-27 OMIM Ambry Genetics 168.9 True BP1,BP4,BP5,BS1,BS2,BS3,BS4 Population frequency, New benign functional evidence
HNF1A NM_000545.8(HNF1A):c.92G>A (p.Gly31Asp) missense 2005-03-01 2017-03-01 OMIM GeneDx 144.0 True BP4,BS1 Population frequency
NPHS1 NM_004646.4(NPHS1):c.559G>A (p.Val187Met) Missense variant in extracellular domain of nephrin protein 2018-09-16 2023-03-02 Gharavi Laboratory, Columbia University Labcorp Genetics (formerly Invitae), Labcorp 53.5 True PP4 Other/Unknown
NPHS1 NM_004646.4(NPHS1):c.559G>A (p.Val187Met) missense 2018-09-16 2023-03-02 Gharavi Laboratory, Columbia University Labcorp Genetics (formerly Invitae), Labcorp 53.5 True PM2,PP3,PP4 BA1,BP4,BS1 Population frequency (BA1 threshold), Computational shift, Guideline/model change
NPHS1 NM_004646.4(NPHS1):c.559G>A (p.Val187Met) missense 2018-09-16 2023-03-02 Gharavi Laboratory, Columbia University Labcorp Genetics (formerly Invitae), Labcorp 53.5 True Other/Unknown
NPHS2 NM_014625.4(NPHS2):c.59C>T (p.Pro20Leu) missense 2003-05-01 2016-03-04 OMIM Women's Health and Genetics/Laboratory Corporation of America, LabCorp 154.1 True PM1,PM2,PP1,PS4 BP4,BP6,BS1,BS2 Population frequency
NPHS2 NM_014625.4(NPHS2):c.59C>T (p.Pro20Leu) missense 2003-05-01 2016-03-04 OMIM Women's Health and Genetics/Laboratory Corporation of America, LabCorp 154.1 True BS1,BS2 Population frequency
PAX2 NM_000278.5(PAX2):c.1058A>C (p.Gln353Pro) missense 2020-01-22 Precision Medicine Center, Zhengzhou University PreventionGenetics, part of Exact Sciences NaN True PM1,PP1,PP3,PP4,PP5 BP4,BP7,BS1 Population frequency, Computational shift, Guideline/model change
PAX2 NM_000278.5(PAX2):c.1058A>C (p.Gln353Pro) missense 2020-01-22 Precision Medicine Center, Zhengzhou University PreventionGenetics, part of Exact Sciences NaN True PM1,PP1,PP3,PP4,PP5 Other/Unknown
PKD1 NM_001009944.3(PKD1):c.971G>T (p.Arg324Leu) missense 1999-07-01 2019-04-19 OMIM ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories 237.6 True Other/Unknown
PKD1 NM_001009944.3(PKD1):c.971G>T (p.Arg324Leu) missense 1999-07-01 2019-04-19 OMIM ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories 237.6 True Other/Unknown
RET NM_020975.6(RET):c.2372A>T (p.Tyr791Phe) missense 2006-08-28 2012-07-13 Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital Biesecker Lab/Clinical Genomics Section, National Institutes of Health 70.5 True Other/Unknown
SCNN1G NM_001039.4(SCNN1G):c.589G>A (p.Glu197Lys) missense 2008-05-28 2017-04-27 OMIM Illumina Laboratory Services, Illumina 107.0 True PP1,PS3 BP4,BS1 Population frequency
TSC2 NM_000548.5(TSC2):c.4639G>A (p.Val1547Ile) missense 2017-04-11 2021-01-19 OMIM Ambry Genetics 45.3 True PM2,PP3,PS3 BP1,BP4,BP5,BS1,BS2,BS3,BS4 Population frequency, Functional (benign evidence), Computational shift
TSC2 NM_000548.5(TSC2):c.1081C>G (p.Leu361Val) missense 2018-08-01 2020-03-20 Liping Wei Laboratory, Peking University GeneDx 19.6 True BP4,BS4 Guideline/model change

Methods & Assumptions